Project III: Summary/Abstract Parkinson disease (PD) is a highly heterogeneous syndrome with marked differences in progression of motor and cognitive features. PD heterogeneity suggests the existence of subgroups, but there is little success to date in subgroup identification. Subgroup identification would advance the critically important goal of enabling focused or appropriately stratified trials and enhance clinical care by providing better prognostic information. In the prior cycle of this Udall Center, we identified specific regional cholinergic deficits underlying distinct gait- balance deficits, reflecting distorted attentional-motor integration (Overall Component, Projects I & II). We used [18F]FEOBV PET to establish a deeply phenotyped non-demented PD cohort including a substantial subgroup with loss of occipital cortical cholinergic afferents. Our findings (Overall Component, Projects II & III) and those of others demonstrate that cholinergic deficits are an important determinant of heterogeneous clinical features and heterogeneous rates of motor progression and cognitive decline, likely caused by distorted integration of attention and other cognitive functions. Based on our results and other data, our central hypothesis is that early loss of occipital cortical cholinergic afferents identifies a PD subgroup with accelerated motor and cognitive decline. We will test this hypothesis with a prospective, longitudinal study of our uniquely phenotyped PD subject cohort. Importantly, we will further test our findings in an independent replication cohort of incident PD subjects that are similarly phenotyped, including with [18F]FEOBV imaging. This unique feature, made possible because of a valuable international collaboration, will ensure that our findings are derived using rigorous methodology. Future assessments of a hypocholinergic PD subgroup would be greatly facilitated by the identification of clinical features reflecting [18F]FEOBV abnormalities. We will also use our extensive phenotypic dataset and modern data-driven methods to identify easily accessible clinical markers of diminished occipital cortical cholinergic afferents in our Udall cohort, and validate these findings in the incident PD cohort. Together with the University of Rochester Udall and a U-M expert in human subject tracking technology, we will also assess in-home sensor evaluations of gait and balance functions as a clinical marker of occipital cortical cholinergic afferent loss. This work is directly responsive to the NINDS PD 2014 Research Report highest priority recommendations calling for development of ?patient stratification tools that define disease signatures of more homogeneous cohorts with emphasis on slow- vs. fast-progressing PD, ? and non-motor symptoms? (Translational Research Recommendation #1), and development of ?companion biomarkers for dopa-resistant features of PD?especially cognitive impairment?? (Clinical Research Recommendation #2). This clinical project addresses one of the needs described in most recent Udall Centers RFA, ?Identification of patient subgroups?to inform clinical trial design.? Drawing directly on our prior studies of disrupted attentional- motor integration in PD secondary to cholinergic system deficits, we will develop useful tools for clinical research and clinical practice.